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Structure-Assisted Design of Drugs Towards HIV-1 and Malaria Targets Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1040 Structure-Assisted Design of Drugs Towards HIV-1 and Malaria Targets Applied on Reverse Transcriptase and Protease from HIV-1 and Plasmepsin II from Plasmodium falciparum BY JIMMY LINDBERG ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2004 !" # $ % # # &$ $' ($ ) * %$' + % ,' ' - ./ % # % ( ) 012. ( % ' / 3 ( & # 012. & 11 # ' / ' ' 62 p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ill min Annika List of Papers My thesis consists of a comprehensive summary based on the following papers, in which they will be referred to by their numbers. I Lindberg, J., Sigurdsson, S., Löwgren, S., Andersson, H. O., Sahl- berg, C., Noreen, R., Fridborg, K., Zhang, H. & Unge, T. (2002) Struc- tural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. Eur. J. Bio- chem. 269 1670-1677. II Mühlman, A., Lindberg, J., Classon, B., Unge, T., Hallberg, A. & Samuelsson, B. (2001) Synthesis of novel, potent, diol-based HIV-1 pro- tease inhibitors via intermolecular pinacol homocoupling of (2S)-2- benzyloxymethyl-4-phenylbutanal. J. Med. Chem 44, 3407-16. III Lindberg, J., Pyring, D., Löwgren, S., Rosenquist, Å., Zuccarello, G., Kvarnström, I., Zhang, H., Vrang, L., Classon, B., Hallberg, A., Samuelsson, B. & Unge, T. (2004) Symmetric fluoro-substituted diol- based HIV-PR inhibitors: Ortho- and meta-fluorinated P1/P1’-benzyloxy side groups significantly improve the anti-viral activity and preserve binding efficacy. Accepted for publication in Eur. J. Biochem. IV Oscarsson, K., Lahmann, M., Lindberg, J., Kangasmetsä, J., Unge, T., Oscarsson, S., Hallberg, A. & Samuelsson, B. (2003) Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'- groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex. Bioorg. Med. Chem. 11, 1107-15. V Lindberg, J., Johansson, P.-O., Rosenquist, Å., Kvarnström, I., Vrang, L., Samuelsson, B. & Unge, T. (2004) Structural study of Plas- mepsin II from Plasmodium falciparum in complex with novel inhibitor comprising bulky P1 side chain – implications for drug design. Manu- script submitted to Protein Science. Articles are reprinted with the permission of the copyright holders Related Papers I Pyring, D., Lindberg, J., Rosenquist, Å., Zuccarello, G., Kvarn- ström, I., Zhang, H., Vrang, L., Unge, T., Classon, B., Hallberg, A. & Samuelsson, B. (2001) Design and synthesis of potent C2-symmetric diol-based HIV-1 protease inhibitors: effects of fluoro substitution. J. Med. Chem. 44, 3083-91. II Johansson, P-O., Lindberg, J., Blackman, M. J., Kvarnström, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist, Å. & Samuelsson, B. (2004) Design and Synthesis of Potent Inhibitors of Plasmepsin I and II: X-ray Crystal Structure of Inhibitor in Complex with Plasmepsin II. Manuscript submitted to J. Med. Chem. III Schaal, W., Karlsson, A., Ahlsen, G., Lindberg, J., Andersson, H. O., Danielson, U. H., Classon, B., Unge, T., Samuelsson, B., Hulten, J., Hallberg, A. & Karlen, A. (2001) Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sul- famide HIV-1 protease inhibitors. J. Med. Chem. 44, 155-69 Contents Introduction.....................................................................................................9 Methods ........................................................................................................11 Preparing for crystallization .....................................................................11 X-ray Crystallography..............................................................................13 Structure-assisted drug design..................................................................17 Human Immunodeficiency Virus-1 ..............................................................18 HIV-1 life cycle........................................................................................18 Anti-HIV-1 chemotherapy...................................................................21 HIV-1 reverse transcriptase......................................................................22 Nucleoside reverse transcriptase inhibitors .........................................23 Non-nucleoside reverse transcriptase inhibitors..................................24 The K103N resistant mutant................................................................25 HIV-1 protease .........................................................................................29 Catalytic mechanism............................................................................29 C2-symmetric diol-based inhibitors ....................................................31 The malaria parasite......................................................................................40 Parasite life cycle .....................................................................................40 Anti-malarial therapy ...............................................................................42 Plasmepsins ..............................................................................................43 Plasmepsin structure and inhibitors.....................................................44 Future perspectives .......................................................................................49 Acknowledgement ........................................................................................50 Sammanfattning ............................................................................................51 References.....................................................................................................53 Abbreviations AIDS Acquired immunodeficiency syndrome HIV-1 Human immunodeficiency virus type 1 PEG Poly-ethylene glycol CD4 Cluster of differentiation 4 gp Glyco-protein RNA Ribonucleic acid CYP Cytochrome P450 DNA Deoxyribonucleic acid PIC Pre-integration complex LTR Long terminal repeats HAART Highly active anti-retroviral therapy FDA Food and drug administration RT Reverse transcriptase PR Protease NRTI Nucleoside reverse transcriptase inhibitors NNRTI Non-nucleoside reverse transcriptase inhibitors NNIBP Non-nucleoside inhibitor binding pocket PI Protease inhibitors Plm Plasmepsin WHO World health organization Amino acids are referred to by their three- or one-letter abbreviations, as shown in the table below. Alanine Ala A Leucine Leu L Arginine Arg R Lysine Lys K Asparagine Asn N Methionine Met M Aspartate Asp D Phenylalanine Phe F Cysteine Cys C Proline Pro P Glutamate Glu E Serine Ser S Glutamine Gln Q Threonine Thr T Glycine Gly G Tryptophan Trp W Histidine His H Tyrosine Tyr Y Isoleucine Ile I Valine Val V Introduction The scene is a typical one. A patient, perhaps you or I, goes to a doctor and gets a prescription. Then a pharmacist fills the prescription, with instructions to take the drug in the prescribed amount and manner over the following days, weeks or months. The scene is repeated over and over again all around the world. In fact, this has become so common among us in the western world that the pills and tablets have come to be taken for granted. However, discovering that drug in the first place is like searching for a needle in a hay- stack. The research process for discovering, developing and testing new drugs is a complicated, time-consuming, and costly one whose end result is never known at the outset. The research runs from basic biomedical investigation of living cells and molecules to applied research that yields new products to improve healthcare. The complexity of the process can be attributed, in part, to the diversity of scientific disciplines involved in finding new drugs. Tradi- tional organic chemists, physiologists and statisticians have been joined in recent years by new kinds of specialists. Biochemists study the chemistry of life processes. Protein crystallographers study the molecules that make up living matter. Toxicologists investigate the chemicals potential side effects. Pharmacologists look at how drugs work. And computer scientists apply the power of their machines to analyze and assess new chemicals. Each disci- pline provides a different way of looking for that needle that has the proper- ties of an inhibitor. In this thesis attempts have been made towards finding inhibitors with good potential as anti-HIV-1 and anti-malarial drugs in order to combat the devastating diseases AIDS and malaria. Globally of today, AIDS and ma- laria are two of the most threatening diseases known to mankind and current
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